1. Field of the Invention
This invention relates generally to compositions and methods for the prevention and treatment of immunomediated inflammatory disorders. More particularly, the invention relates to the prevention and treatment of inflammatory diseases associated with the respiratory tract, such as asthma and allergic rhinitis. The compositions and methods of the present invention are especially useful for preventing or treating the late phase bronchoconstriction and airway hyperresponsiveness associated with chronic asthma.
2. Description of the Background Art
Asthma is a complex disease involving multiple biochemical mediators for both its acute and chronic manifestations. Asthma frequently is characterized by progressive development of hyperresponsiveness of the trachea and bronchi to both immunospecific allergens and generalized chemical or physical stimuli. The hyperresponsiveness of asthmatic bronchiolar tissue is believed to result from chronic inflammation reactions, which irritate and damage the epithelium lining the airway wall and promote pathological thickening of the underlying tissue. Bronchial biopsy studies have indicated that even patients with mild asthma have features of inflammation in the airway wall.
One initiator of the inflammatory sequence is an allergic response to inhaled allergens. Leukocytes carrying IgE receptors, notably mast cells and basophils, but also including monocytes, macrophages, and eosinophils, are present in the epithelium and underlying smooth muscle tissues of bronchi, where they are activated initially by binding of specific inhaled antigens to the IgE receptors. Activated mast cells release a number of preformed or primary chemical mediators of the inflammatory response and enzymes. Furthermore, numerous secondary mediators of inflammation are generated in situ by enzymatic reactions of activated mast cells, including superoxide and lipid derived mediators. In addition, several large molecules are released by degranulation of mast cells: proteoglycans, peroxidase, arylsulfatase B, and notably the proteases tryptase and chymotryptic proteinase (chymase). See "Drug Therapy of Asthma", Chap. 62, 1054-54.
This chemical release from mast cells probably accounts for the early bronchiolar constrictor response that occurs in susceptible individuals after exposure to airborne allergens. The early asthmatic reaction is maximal at around fifteen minutes after allergen exposure; recovery occurs over the ensuing one to two hours. In 25-35% of individuals, the early asthmatic reaction is followed by a further decline in respiratory function which begins within a few hours and is maximal between six and twelve hours post-exposure. This late asthmatic reaction is accompanied by a marked increase in the number of inflammatory cells infiltrating bronchiolar smooth muscle and epithelial tissues, and spilling into the airways. These cells include eosinophils, neutrophils, and lymphocytes, all of which are attracted to the site by release of mast cell derived chemotactic agents. The infiltrating cells themselves become activated during the late reaction phase. The late asthmatic response is believed to be a secondary inflammatory reaction mediated in part by the secretory activity of macrophages.
A related set of inflammatory reactions occurs in the upper respiratory tract mucosa, usually in response to airborne allergens. As in asthma, mast cells are activated by crosslinking of IgE molecules to particular antigens. In allergic, perennial or vasomotor rhinitis, mast cells may be activated in the absence of discernible exposure to a particular antigen. In either case, activated mast cells release primary and secondary mediators of inflammation upon degranulation. Eosinophils and macrophages are attracted to the site to perpetuate the inflammation reaction. Nasal epithelial tissue destruction often occurs in late-phase reactions.
Tryptase is the major secretory protease of human mast cells and is proposed to be involved in neuropeptide processing and tissue inflammation. Mature human tryptase is a glycosylated, heparin-associated tetramer of heterogenous, catalytically active subunits. The tryptase monomer's amino acid sequence, like its gene structure, has no close counterpart among the numerous other serine proteinases that have been characterized. See, e.g., Vanderslice et al. (1990) Proc. Natl. Acad. Sci. USA 87:3811-3815; Miller et al. (1990) J. Clin. Invest. 86:864-870; Miller et al. (1989) J. Clin. Invest. 84:1188-1195; and Vanderslice et al. (1989) Biochemistry 28:4148-4155.
Tryptase is stored in mast cell secretory granules. After mast cell activation, human tryptase can be measured readily in a variety of biologic fluids. For example, after anaphylaxis, tryptase appears in the bloodstream, where it remains detectable for several hours. See Schwartz et al. (1987) N. Engl. J. Med. 316:1622-1626. Its appearance has been detected in samples of nasal and lung lavage fluid from atopic subjects challenged with specific antigen. See Castells and Schwartz 1988) J. Allerg. Clin. Immunol. 82:348-355 and Wenzel et al. (1988) Am. Rev. Reap. Dis. 141:563-568. Tryptase levels in lung lavage fluid obtained from atopic asthmatics increase after endobronchial allergen challenge. Id. Some smokers of cigarettes have striking elevations of bronchoalveolar lavage fluid tryptase levels compared to nonsmoking controls, a finding that provides some support for the hypothesis that release of proteinases from activated mast cells could contribute to lung destruction in smoker's emphysema. See Kalenderian et al. (1988) Chest 94:119-123. In addition, tryptase has been shown to be a potent mitogen for fibroblasts, suggesting its involvement in pulmonary fibrosis and interstitial lung diseases. See Ruoss et al. (1991) J. Clin. Invest. 88:493-499.
Tryptase has been implicated in a variety of biological processes, including degradation of vasodilating and bronchorelaxing neuropeptides (see Caughey et al. (1988) J. Pharmacol. Exp. Ther. 244:133-137; Franconi et al. (1988) J. Pharmacol. Exp. Ther. 248:947-951; and Tam et al. (1990) Am. J. Respir. Cell Mol. Biol. 3:27-32) and modulation of bronchial responsiveness to histamine (see Sekizawa et al. (1989) J. Clin. Invest. 83:175-179). These studies suggest that tryptase possibly increases bronchoconstriction in asthma by destroying bronchodilating peptides.
Additionally, tryptase has been shown to cleave fibrinogen .alpha.-chains, as well as high molecular weight kininogen with a possible release of kinins and thus, may play a role with heparin as a local anticoagulant. The ability of tryptase to activate prostromelysin (pro-MMP-3) and procollagenase (pro-MMP-1) via MMP-3 suggests that tryptase also may be involved in tissue inflammation and remodeling. This finding also intimates that tryptase may play a role in joint destruction in rheumatoid arthritis. In addition, tryptase has been shown to cleave calcitonin gene-related peptide. As this peptide is implicated in neurogenic inflammation, tryptase could be a factor in the regulation of flare reaction in cutaneous neurogenic inflammation. See Caughey (1991) Am. J. Respir. Cell Mol. Biol. 4:387-394.
Asthma has become the most common chronic disease in industrialized countries. To date, conventional methods and therapeutic agents have not proved to be effective in the treatment of asthma or other immunomediated inflammatory disorders. For these reasons it would be desirable to provide improved compositions and methods which avoid the disadvantages of these conventional agents and methods while providing effective treatment for these diseases.